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J E Torres

Publications and source records attributed to J E Torres.

At least 19 recordsLinked to original sources
PubMed2001

Brainstem nitric oxide tissue levels correlate with anoxia-induced gasping activity in the developing rat.

Gasping is an important mechanism for survival that appears to be developmentally modulated by the glutamate-nitric oxide (NO) pathway. However, the temporal characteristics of NO brain tissue levels during gasping are unknown. We hypothesized that during anoxia-induced gasping, the gasping frequency would be closely correlated with caudal brainstem tissue NO concentrations in developing rats. Brainstem and cortical tissue NO levels were measured during anoxia using a voltammetric electrode in adult rats and 5-day-old pups during control conditions and following pretreatment with the NMDA receptor antagonist MK-801 (1 mg/kg) or the neuronal NO synthase inhibitor 7-nitro-indazole (7-NI; 100 mg/kg). In young animals, NO tissue levels followed a triphasic trajectory coincident with gasp frequency which was markedly altered by MK-801 and 7-NI, albeit with preservation of gasp frequency-NO tissue level relationships. In adult rats, 40-fold higher NO tissue levels occurred and followed a monophasic trajectory coincident with gasp patterning. In the cortex, monophasic increases in NO levels occurred at all ages. We conclude that anoxia-induced gasping neurogenesis is modulated via NMDA-NO mechanisms in the developing rat. We postulate that higher NO brainstem concentrations may favor early autoresuscitation, but limit anoxic tolerance.

Aging↗
PubMed1999

Short-term potentiation of ventilation after different levels of hypoxia.

Short-term potentiation of ventilation (VSTP) may be observed in healthy subjects on sudden termination of an hypoxic stimulus. We hypothesized that the level of hypoxia preceding normoxia would modify the duration and magnitude of the ensuing ventilatory decay. Ten healthy adults were studied on two different occasions, during which they were randomly exposed to isocapnic 6 or 10% O2 for 60 s and then switched to an isocapnic normoxic gas mixture. Both hypoxic gases induced significant ventilatory responses, and mean peak minute ventilation before the isocapnic normoxic switch was higher in 6% O2 (P < 0.001). The fast time constant of the two-exponential equation representing the best fit for ventilatory decay was unaffected by the magnitude of the hypoxic stimulus. However, the slow time constant, which is considered to represent VSTP, was markedly prolonged in 6% compared with 10% O2 [106.7 +/- 11.3 vs. 38. 2 +/- 6.1 (SD) s, respectively; P < 0.0001]. This result indicates that VSTP is stimulus dependent. We conclude that the magnitude of hypoxia preceding a normoxic transient modifies VSTP characteristics. We speculate that the interdependence function of ventilatory stimulus and short-term potentiation is crucial for preservation of system stability during transitions from high to low ventilatory drives.

Adult↗
PubMed1998

Selective inhibitors of human lactate dehydrogenases and lactate dehydrogenase from the malarial parasite Plasmodium falciparum.

Derivatives of the sesquiterpene 8-deoxyhemigossylic acid (2, 3-dihydroxy-6-methyl-4-(1-methylethyl)-1-naphthoic acid) were synthesized that contained altered alkyl groups in the 4-position and contained alkyl or aralkyl groups in the 7-position. These substituted dihydroxynaphthoic acids are selective inhibitors of human lactate dehydrogenase-H (LDH-H) and LDH-M and of lactate dehydrogenase from the malarial parasite Plasmodium falciparum (pLDH). All inhibitors are competitive with the binding of NADH. Selectivity for LDH-H, LDH-M, or pLDH is strongly dependent upon the groups that are in the 4- and 7-positions of the dihydroxynaphthoic acid backbone. Dissociation constants as low as 50 nM were observed, with selectivity as high as 400-fold.

Animals↗
PubMed1998

Modulation of the hypoxic ventilatory response by Ca2+-dependent and Ca2+-independent protein kinase C in the dorsocaudal brainstem of conscious rats.

Protein kinase C (PKC) activation in the nucleus tractus solitarii (NTS) is critical for mounting an appropriate hypoxic ventilatory response (HVR). Furthermore, hypoxia elicits translocation of both Ca2+-dependent and Ca2+-independent PKC isoforms in the NTS. However, the relative functional contribution of such PKC isoforms in mediating HVR is unclear. To study these issues, chronically instrumented adult Sprague-Dawley rats underwent hypoxic challenges (10% O2 balance in N2) following dorsocaudal brainstem microinjections of the selective Ca2+-dependent PKC inhibitor Gö 6976 (10 mmol in 1 microl). Compared with vehicle, Gö 6976 did not modify normoxic ventilation but maximally attenuated HVR by 38.4 +/- 6.7% (n = 9; P < 0.01), with similar contributions from tidal volume and respiratory frequency. In seven additional animals, when the non Ca2+-selective PKC blocker BIM I was concurrently microinjected with Gö 6976, further reductions in peak ventilatory responses to hypoxia occurred (P < 0.04). When BIM V, the inactive analog, was microinjected with Gö 6976, the magnitude of HVR attenuation was unchanged (n = 6; Gö 6976 vs. Gö 6976 + BIM V: P = NS). We conclude that in the dorsocaudal brainstem, PKC-mediated components of HVR involve activation of both Ca2+-dependent and Ca2+-independent PKC isoforms.

Animals↗
PubMed1998

Modulation of hypoxic ventilatory response by systemic platelet-activating factor receptor antagonist in the rat.

Platelet activating factor (PAF) has recently emerged as an important modulator of neuronal excitability by enhancing synaptic glutamate release. Since PAF receptors (PAFR) are ubiquitously distributed in the brain, we hypothesized that PAF may play a role in respiratory control. To examine this issue, hypoxic (10% O2 for 15 min, n = 14) and hypercapnic (5% CO2 for 30 min, n = 6) challenges were performed in chronically-instrumented, unrestrained adult rats following administration of the pre-synaptic PAFR antagonist BN52021 (i.p. 20 mg/kg in 0.5 ml) or vehicle (Veh). In normoxia, BN52021 elicited VT decreases and corresponding f increases such that minute ventilation (VE) was unaffected. During hypercapnia, peak VE increased similarly after both treatments (103+/-18% in BN52021 vs. 94+/-19% in Veh, p-NS). In contrast, significant reductions in the peak hypoxic VE response occurred after BN52021 (42+/-10% vs. 104+/-18% in Veh, P<0.002). BN52021 increased normoxic arterial blood pressure and decreased heart rate. However, hypoxia-induced chronotropic responses were attenuated and depressor responses were enhanced by BN52021. We further examined protein kinase C (PKC) translocation patterns during acute hypoxia after systemic BN52021 administration. Activation of PKC beta and delta was blocked by BN52021, PKC gamma was attenuated, with no effects on PKC alpha, epsilon, theta, iota, mu, and zeta. We conclude that systemic administration of a PAFR antagonist attenuates cardioventilatory recruitment to hypoxia and selectively attenuates activation of PKC in the rat brainstem. We speculate that enhanced regional PAF production and release during hypoxic conditions may contribute important excitatory inputs and signal transduction pathways within neuronal structures underlying cardiovascular and respiratory control.

Animals↗
PubMed1998

Histopathologic differentiation between localized and systemic scleroderma.

It is widely accepted that a histopathologic differentiation between localized scleroderma (LS) and systemic scleroderma (SS) is not always possible. With the objective of identifying differentiating histopathological features between them, 32 cases of LS and 19 cases of SS were reviewed. Histological features such as the distribution, composition, and density of the inflammatory cell infiltrate, thickness of the dermis, alterations of dermal collagen, and the presence of calcification were evaluated in each case. On the basis of our observations, LS and SS can be differentiated usually by the distribution and density of the inflammatory infiltrate and by the involvement of the papillary dermis. Inflammatory changes are more prominent in LS than in SS. Sclerosis of the papillary dermis is frequently seen in LS but is absent in SS.

Adolescent↗
PubMed1998

Platelet-activating factor modulates cardiorespiratory responses in the conscious rat.

Platelet-activating factor receptor (PAFR) activation is associated with increases in neuronal excitability. We hypothesized that PAF may play a role in cardiorespiratory control. Ventilatory responses to microinjection of a long-acting PAF analog (mc-PAF, 1 microg in 1 microl) within the dorsocaudal brain stem were measured in unrestrained adult rats. mc-PAF elicited significant minute ventilation (VE) enhancements that were primarily due to tidal volume increases and were accompanied by respiratory alkalosis, heart rate increase, and reduction of arterial blood pressure. Such cardiovascular and respiratory effects did not occur after administration of either vehicle or the inactive analog lyso-PAF. The effect was blocked when animals were coadministered the presynaptic PAFR antagonist BN-52021 or recombinant PAF acetyl hydrolase. To determine the relative contribution of PAF to hypercapnic and hypoxic ventilation, microinjections were performed in additional animals with either vehicle (CO, 1 microl) or with 5 microg in 1 microl of BN-52021. Hypercapnic challenges with 5% CO2 were unaffected by BN-52021. In contrast, although 10% O2 breathing increased VE from 120.4 +/- 7.5 to 204.6 +/- 11.4 ml/min in CO, after BN-52021, VE increased only from 118.7 +/- 6.9 to 137.3 +/- 8. 9 ml/min (CO vs. BN-52021, P < 0.001). We conclude that PAFR activation in the dorsocaudal brain stem exerts significant cardioventilatory effects during normoxia and appears to play an important modulatory role in the VE response to hypoxia in conscious rats.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1998

Cardiorespiratory responses to systemic administration of a protein kinase C inhibitor in conscious rats.

Although protein kinase C (PKC) is an essential component of multiple neurally mediated events, its role in respiratory control remains undefined. The ventilatory effects of a systemically active PKC inhibitor (Ro-32-0432; 100 mg/kg i.p.) were assessed by whole body plethysmography during normoxia, hypoxia (10% O2), and hyperoxia (100% O2) in unrestrained Sprague-Dawley rats. A sustained expiratory time increase occurred within 8-10 min of injection in room air[mean 44.8 +/- 5.2 (SE) % ], was similar to expiratory time prolongations after Ro-32-0432 administration during 100% O2 (45.5 +/- 8.1%; not significant), and was associated with mild minute ventilation (VE) decreases. Hypercapnic ventilatory responses (5% CO2) remained unchanged after Ro-32-0432. During 10% O2, VE increased from 122.6 +/- 15.6 to 195.7 +/- 10.1 ml/min in vehicle-treated rats (P < 0.001). In contrast, marked attenuation of VE hypoxic responses occurred after Ro-32-0432 [86.2 +/- 6.2 ml/min in room air to 104.1 +/- 7.1 ml/min in 10% O2; pre- vs. post-Ro32-0432, P < 0.001 (analysis of variance)]. Overall, PKC activity was reduced and increases with hypoxia were abolished in the particulate subcellular fraction of brain tissue after Ro-32-0432 treatment, indicating that this compound readily crosses the blood-brain barrier. We conclude that systemic PKC inhibition elicits significant centrally mediated expiratory prolongations and ventilatory reductions as well as blunted ventilatory responses to hypoxia but not to hypercapnia. We postulate that PKC plays an important role in signal transduction pathways within brain regions underlying respiratory control.

Animals↗
PubMed1998

NMDA receptors mediate peripheral chemoreceptor afferent input in the conscious rat.

N-methyl-D-aspartate (NMDA) glutamate receptors mediate critical components of cardiorespiratory control in anesthetized animals. The role of NMDA receptors in the ventilatory responses to peripheral and central chemoreceptor stimulation was investigated in conscious, freely behaving rats. Minute ventilation (VE) responses to 10% O2, 5% CO2, and increasing intravenous doses of sodium cyanide were measured in intact rats before and after intravenous administration of the NMDA receptor antagonist MK-801 (3 mg/kg). After MK-801, eupcapnic tidal volume (VT) decreased while frequency increased, resulting in a modest reduction in VE. Inspiratory time (TI) decreased, whereas expiratory time remained unchanged. The VE responses to hypercapnia were qualitatively similar in control and MK-801 conditions, with slight reductions in respiratory drive (VT/TI) after MK-801. In contrast, responses to hypoxia were markedly attenuated after MK-801 and were primarily due to reduced frequency changes, whereas VT was unaffected. Sodium cyanide doses associated with significant VE increases were 5 and 50 microg/kg before and after MK-801, respectively. Thus 1-log shift to the right of individual dose-response curves occurred with MK-801. Selective carotid body denervation reduced VE during hypoxia by 70%, and residual hypoxic ventilatory responses were abolished after MK-801. These findings suggest that, in conscious rats, carotid and other peripheral chemoreceptor-mediated hypoxic ventilatory responses are critically dependent on NMDA receptor activation and that NMDA receptor mechanisms are only modestly involved during hypercapnia.

Animals↗
PubMed1998

Protein kinase C modulation of ventilatory response to hypoxia in nucleus tractus solitarii of conscious rats.

This study aimed to determine the role of protein kinase C (PKC) in signal transduction mechanisms underlying ventilatory regulation in the nucleus tractus solitarii (NTS). Microinjection of phorbol 12-myristate 13-acetate into the commissural NTS of nine chronically instrumented, unrestrained rats elicited significant cardiorespiratory enhancements that lasted for at least 4 h, whereas administration of vehicle (n = 15) or the inactive phorbol ester 4alpha-phorbol 12,13-didecanoate (n = 7) did not elicit minute ventilation (VE) changes. Peak hypoxic VE responses (10% O2-balance N2) were measured in 19 additional animals after NTS microinjection of bisindolylmaleimide (BIM) I, a selective PKC inhibitor (n = 12), BIM V (inactive analog; n = 7), or vehicle (Con; n = 19). In Con, VE increased from 139 +/- 9 to 285 +/- 26 ml/min in room air and hypoxia, respectively, and similar responses occurred after BIM V. BIM I did not affect room air VE but markedly attenuated hypoxia-induced VE increases (128 +/- 12 to 167 +/- 18 ml/min; P < 0. 02 vs. Con and BIM V). When BIM I was microinjected into the cerebellum (n = 4), cortex (n = 4), or spinal cord (n = 4), VE responses were similar to Con. Western blots of subcellular fractions of dorsocaudal brain stem lysates revealed translocation of PKCalpha, beta, gamma, delta, epsilon, and iota isoenzymes during acute hypoxia, and enhanced overall PKC activity was confirmed in the particulate fraction of dorsocaudal brain stem lysates harvested after acute hypoxia. These studies suggest that, in the adult rat, PKC activation in the NTS mediates essential components of the acute hypoxic ventilatory response.

Animals↗
PubMed1998

Nitric oxide modulates anoxia-induced gasping in the developing rat.

Gasping is an important mechanism for survival. Nitric oxide (NO) plays an excitatory role in brainstem regions mediating respiratory responses to hypoxia. We hypothesized that neural structures mediating anoxia-induced gasping would display NO dependency. Two- to 15-day-old rat pups underwent anoxic exposures with 100% N2 in a plethysmograph following administration of N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) blocker, L-arginine (L-Arg), a NO precursor, or normal saline. In general, gasp latencies were significantly shorter after L-Arg, and were prolonged with L-NAME. Furthermore, NOS inhibition prolonged gasping duration and reduced gasping frequency at all postnatal ages, although this effect was particularly increased with advancing postnatal age. NADPH-diaphorase staining and Western blots of protein lysates from the lateral tegmental field, the putative neural center underlying gasp generation, revealed progressively increased neuronal NOS abundance with animal maturation. We conclude that anoxia-induced gasping neurogenesis is modulated by NO mechanisms in neonatal pups. We postulate that higher NO brainstem concentrations may favor early autoresuscitation but be detrimental to overall survival during prolonged asphyxia.

Animals↗
PubMed1997

Nitric oxide modulates in vitro intrinsic optical signal and neural activity in the nucleus tractus solitarius of the rat.

Nitric oxide (NO) is a novel neurotransmitter with important cardiorespiratory functions. To determine the functional topography of NO in a brainstem preparation, extracellular and intrinsic optical signal recordings were simultaneously acquired from a 300 microm coronal brainstem slice at the level of the obex. During control conditions, spontaneous spike activity in the nucleus tractus solitarius (NTS) was 6.2 +/- 1.4 Hz. When the competitive NOS inhibitor, L-NAME, was applied to the bath (1 mM), spike activity either ceased or was markedly reduced in frequency (1.2 +/- 0.7 Hz; n = 7; P < 0.01). The decrease in activity was reversed when the NOS substrate L-arginine (L-Arg) was added to the bath (9.4 +/- 1.8 Hz; P < 0.04). Concurrent intrinsic optical signal imaging of the slice preparation consistently revealed coincident decreases in activity within the NTS with L-NAME (deltaT/T: -2.4 +/- 0.9%; P < 0.02), and increases with L-Arg (+2.1 +/- 0.8%; P < 0.04). Such changes were absent in other regions such as the hypoglossal nuclei or area postrema. We conclude that in this brainstem region, NO modulation of neuronal activity is primarily circumscribed to the NTS.

Animals↗
PubMed1997

Nitric oxide modulates ventilatory responses to hypoxia in the developing rat.

Nitric oxide (NO) is an important excitatory neurotransmitter in the central nervous system. In the adult rat, both selective and nonselective blockers of constitutive nitric oxide synthase (NOS) induce marked ventilatory reductions during sustained hypoxia, thereby enhancing ventilatory roll-off. Since hypoxic ventilatory depression is greater in developing mammals during the late phases of hypoxic exposure, we hypothesized that limited NOS activity may play a role in the late arm of the ventilatory response. To test our hypothesis, 5-d-, 10-d-, and 15-d-old rat pups underwent a 30-min hypoxic challenge (10% O2) before and after administration of 100 mg/kg N-nitro-L-arginine methyl ester (L-NAME), a competitive NOS inhibitor. Minute ventilation (VE) was measured using whole-body plethysmography. In 5-d-old pups, early VE hypoxic responses were enhanced, and late VE were similar after administration of L-NAME. In contrast, in 15-d-old hypoxic pups, L-NAME administration was associated with smaller early VE increments and significantly larger VE reductions when compared with pretreatment conditions. The role of central nervous system NO in the development of these ventilatory changes was further assessed by Western blots of protein equivalents from the nucleus tractus solitarius (NTS), the first central relay for peripheral chemoreceptor afferent input, which revealed increasing neuronal NOS expression with age. Furthermore, NADPH-diaphorase immunohistochemical staining of neurons in the NTS revealed increased positively labeled neuronal populations within subnuclei of this structure with advancing postnatal age. Current findings suggest that NOS activity mediates both excitatory and inhibitory components of the hypoxic ventilatory response. Furthermore, in brainstem respiratory regions, NO may play a role in modulating the prominent second phase of the biphasic response to hypoxia typically seen in early postnatal life.

Aging↗
PubMed1997

Maturation of anoxia-induced gasping in the rat: potential role for N-methyl-D-aspartate glutamate receptors.

After anoxia-induced apnea, gasping remains the last operative mechanism for survival. In developing rats, the gasping response to anoxia exhibits triphasic characteristics. Because anoxia is associated with enhanced release of glutamate, we hypothesized that N-methyl-D-aspartate (NMDA) glutamate receptors may underlie components of the gasping response. Rat pups aged 2 d (n = 50), 5 d (n = 43), 10 d (n = 42), and 15 d (n = 45) underwent anoxic challenges with 100% N2 in a whole body plethysmograph, 30 min after intraperitoneal administration of MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate; dizocilpine] (3 mg/kg), a noncompetitive NMDA glutamate receptor channel antagonist, or normal saline. In control pups, after primary apnea onset, a triphasic gasping pattern was apparent at all postnatal ages and included two distinct types of gasps (I and II). In 2- and 5-d MK801-treated animals, phase 1 and type I gasps were absent, leading to marked prolongations of the gasp latency and phase 2, the latter displaying type II gasps only. In addition, phase 3 duration was also prolonged with increased type II gasp frequencies. In contrast, in some 10-d-old (40%) and in all 15-d-old MK801-treated pups, although overall gasping duration was prolonged, the triphasic gasping pattern seen in matched controls was also present. We conclude that NMDA glutamate receptors mediate particular phasic components of the gasping response during early postnatal life but not at later stages of development. We speculate that developmental changes occur in both function and expression of NMDA and other neurotransmitters within brainstem regions underlying the neural substrate for gasp generation.

Analysis of Variance↗
PubMed1996

Nitric oxide synthase isoforms and peripheral chemoreceptor stimulation in conscious rats.

To test the effect of nitric oxide synthase (NOS) blockade on the ventilatory responses to carotid body chemoreceptor stimulation in freely behaving animals, chronically instrumented adult Sprague-Dawley rats received increasing intravenous doses of sodium cyanide (NaCN; 0-300 micrograms kg-1) before and after i.v. administration of either 100 mg kg-1 N-nitro-L-arginine methyl ester (L-NAME), a non-specific NOS blocker, or 10 mg kg-1 S-methyl-L-thiocitrulline (SMTC), a selective neuronal NOS inhibitor. SMTC did not modify the NaCN dose-response curve. In contrast, L-NAME significantly enhanced the ventilatory responses to NaCN. Western blots of equivalent amounts of protein from carotid body tissue homogenates revealed higher levels of endothelial NOS than of neuronal NOS. We conclude that endothelial NOS provides the major source for NO within the carotid body, and exerts a down-regulatory effect upon peripheral chemoreceptor responsivity.

Animals↗